Ligand-accelerated non-directed C-H functionalization of arenes

Abstract

The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.

Figure 1. C–H functionalization of arenes

a, Pd-catalyzed Csp²–H functionalization. DG, directing group. b, Ligand-accelerated Pd-catalyzed C–H functionalization. L; Ligand. DFT-optimized C–H activation transition state at the M06/SDD,6-311+G(d,p)(SMD)//B3LYP/LANL2DZ,6-31G(d) level of theory. c, Crystal structure of Pd/L69. d, Ligand effects on reactivity and site selectivity for selected substrates. HFIP, hexafluoroisopropanol. CHCl₃, chloroform.

Figure 2. The C–H olefination of arenes and heterocycles

TBS, tert-butyldimethylsilyl; TIPS, triisopropylsilyl; Pin, pinacolate; Ts, 4-toluenesulfonyl. The values under each structure indicate isolated yields. Reaction conditions: Pd(OAc)₂ (10 mol%), L69 (30 mol%), AgOAc (3.0 equiv.), HFIP (0.5 mL), 100 °C, 24 h; For 3a, 3r, 3t, 3w, 3y, 3ai, 3aj, 3ak, 3an, 3ao, 3ay, 3az and 3bb, CHCl₃ (0.5 mL) was used instead of HFIP; For 3j and 3k, L31 (20 mol%) was used instead of L69; For 3l and 3ab, Pd(OAc)₂ (20 mol%), L69 (60 mol%), and ethyl acrylate (1.2 equiv.) were used; For 3as–3ax, the reaction was conducted at 90 °C; For 3al, 3am, 3aq and 3ar, Ag₂CO₃ (1.5 equiv.) was used instead of AgOAc; For 3am, the reaction time was shortened to 12 h; For 3ap, the reaction was conducted at 60 °C; For 3ar, the reaction time was shortened to 8 h. For 3bd, substrates (0.2 mmol), ethyl acrylate (0.1 mmol) were used in CHCl₃.

Figure 3. The scope of olefin partners and carboxylation

a, Scope of olefin coupling partners. HFIP, hexafluoroisopropanol. Reaction conditions: o-xylene (0.1 mmol), olefin (2.0 equiv.), Pd(OAc)₂ (10 mol%), L69 (30 mol%), AgOAc (3.0 equiv.), HFIP (0.5 mL), 100 °C, 24 h. For 4a–4d, 4i, 4l, 4p, the reaction was conducted in HCCl₃; for 4c, the reaction time was shortened to 16 h. b, Carboxylation of simple arenes. Phth, Phthaloyl. Reaction conditions: Substrate (0.2 mmol), CO (1 atm), Pd(OAc)₂ (10 mol%), L (30 mol%), AgOAc (3.0 equiv.), HFIP (2.0 mL), 100 °C, 24 h; then NaOH (1.5 mL, 2 M), MeOH (2.0 mL), 12 h. For 5d and 5e, substrate (0.1 mmol) was used; for 5c and 5d, the products were isolated before hydrolysis.

Figure 4. Late-stage functionalization of natural products and drug molecules

Phth, Phthaloyl; TBS, tert-butyldimethylsilyl; Ts, 4-toluenesulfonyl; HFIP, hexafluoroisopropanol. The values under each structure indicate isolated yields. Reaction conditions: Substrate (0.1 mmol), Ethyl acrylate (0.2 mmol), Pd(OAc)₂ (10 mol%), L69 (30 mol%), AgOAc (3.0 equiv.), HFIP (0.5 mL), 100 °C, 24 h. For 7d, 7f, and 7i, the reaction was conducted for 16 h. For 7g, chloroform was used instead of HFIP.